Method for the preparation of derivatives of 5-hydro xy-2-carboxychromone

ABSTRACT

WHEREIN X is an aliphatic alkyl having from C3 to C7 with its chain possibly interrupted by an oxygen atom and preferably containing a secondary alcoholic grouping, by alkaline hydrolysis of the corresponding lower alkyl ester, the latter being prepared starting from the corresponding bis-phenoxy derivative (a) by double Claisen reaction with an alkyl oxalate in the presence of an alkali metal alcoholate as the catalyst, and (b) by cyclizing the intermediate thus obtained in an acidic environment, the improvement consisting in that the reaction with the alkyl oxalate is carried out in an alcoholic protic solvent in the presence of stoichiometric amounts of the alkali metal alcoholate at a temperature not above 50*C and for a time not longer than 3 hours, the cyclization being carried out by adding an anhydrous mineral acid to the reaction mass. By so doing, the preparation of the expected compounds is cheaper, quicker and gives virtually quantitative yields.   A method for the preparation of derivatives of the 5-hydroxy-2carboxychromone is disclosed, said derivatives having the general formula

United States Patent [191 Pifferi [111 3,843,687 51 Oct. 22, 1974 METHODFOR THE PREPARATION OF DERIVATIVES OF S-HYDRO XY-Z-CARBOXYCHROMONEGiorgio Pifferi, Milan, Italy [73] Assignee: I.S.F., S.p.A., Milan,Italy [22] Filed: June 6, 1972 [75] Inventor:

' [21] Appl. No.: 260,273

[30] Foreign Application Priority Data July 2, 1971 Italy 26560/71 [52]U.S. Cl. 260/345.2, 424/283 [51] Int. Cl C02d 7/34] [58] Field of Search260/3452 [56] References Cited UNITED STATES PATENTS l2/l968 Fitzmauriceet al. 260/3452 Primary Examiner-John M. Ford Attorney, Agent, orFirm--Shlesinger, Fitzsimmons & Shlesinger [57] ABSTRACT A method forthe preparation of derivatives of the 5-hydroxy-2-carboxychrom one isdisclosed, said derivatives having the general formula O-X- O 0 H00 0COOH wherein X is an aliphatic alkyl having from C,, to C with its chainpossibly interrupted by an oxygen atom and preferably containing asecondary alcoholic grouping, by alkaline hydrolysis of thecorresponding lower alkyl ester, the latter being prepared starting fromthe corresponding bis-phenoxy derivative (a) by double Claisen reactionwith an alkyl oxalate in the presence of an alkali metal alcoholate asthe catalyst,

and (b) by cyclizing the intermediate thus obtained in,

3 Claims, No Drawings METHOD FOR THE PREPARATION OF DERIVATIVES OFS-HYDRO XY-Z-CARBOXYCHROMONE This invention relates to a novel methodfor preparing duplication derivatives of 5-hydroxy-2-carboxychromonehaving the general formula:

I o 0 x 0 HOOC COOH wherein X is either a linear or branched aliphaticradical having from C to C1, preferably containing a secondary alcoholicgrouping and possibly interrupted by an oxygen atom.

It is known that the compounds (I) and their salts with appropriateorganic and inorganiccations which are physiologically acceptablepossess particular pharmacological properties, inasmuch as they act asinhibia. The use of an aprotic solvent, admixed or not with limitedamounts of ethanol (for example: benzeneethanol) b. Refluxing thesuspension c. Long reaction times, up to 20-24 hours d. An excess ofalcoholate, preferably sodium ethoxide e. Isolation and purification ofthe intermediate (W) and subsequent cyclization to chrozmone (ll).

These conditions correspond to those which are well known as suggestedby the technical literature for optimizing the Claisen reaction. As amatter of fact, the notors of the complex antigen-antibody reactions inthe toriously accepted mechanism for sucha reaction:

Ro HCH wherein R is a lower alkyl radical and X has the meaning asdefined hereinabove. The compounds (II) in turn, since they aresymmetrical derivatives of hydroxychromones, are preferably preparedstarting from the corresponding bis-phenoxy derivatives having theformula (ill):

' teaches that an excess of alcoholate RO and stripping the alcoholshould shift the equilibrium towards the right, thus encouraging theformation of the reactive anion (cf., for example, J. D. Roberts et al.,Basic Principles of Organic Chemistry Benjamin Inc, New York, 1965, page538).

An essential aspect of the present invention is to improve to asubstantial degree the preparation of the esters having the formula(II), so as to allow extremely bland operative conditions while avoidingthe concurrent decomposition and resinification process which areconducive to unsatisfactory yields and to less pure end products aswell. According to another facet of the present invention, it isprovided that the conversion of the derivatives having the formula (lll)into the cyclic esters having the formula (11) may occur at a single-CODR i7 COCII C coon R006 2 temperature.

As a matter of fact, a method has been found, for the synthesis ofderivatives of 5-hydroxy-2-carboxychroq s a i eses??? fa 0 0 X 0 ll 9 0coon Wherein X is an aliphatic radical having from C to C possiblyhaving its chain interrupted by an oxygen atom and containing, ipreferably, a secondary alcoholic grouping, by alkaline hydrolysis ofthe corresponding ester having the general formula:

COOR

wherein R is a lower alkyl radical and X has the meaning as definedhereinabove, said ester being prepared starting from the correspondingbis-phenoxy derivative by double Claisen reaction with an alkyl oxalatein the presence of an alkaline catalyst and cyclization of theintermediate product thus obtained in an acidic environment,characterized in that the reaction with the alkyl oxalate is carried outin an alcoholic protic solvent in the presence of stoichiometric amountsof an alkali metal alcoholate, at a temperature not higher than 50C andfor a time of not more than 3 hours, the cyclization being performed bymerely adding an anhydrous mineral acid to the reaction mass.

In substance, the novel method according to the present invention ischaracterized:

a. by the use of a protic solvent, such as methanol, ethanol, propanol,etc., in an absolute absence of aprotic solvents.

b. in that the reaction takes place, preferably, at room temperature,but the temperature can be raised to 40-50C.

c. in that the reaction times are at least twenty times a submultiple ofthose required by the conventional cent of theory), and to thesignificant reduction of the reaction times and temperatures (with theattendant reduction of running costs), also the quality of the endproduct is considerably improved.

It is known, in fact, that the Claisen reaction is reversible(back-Claisen) and that the oxalyl derivatives of the kind (IV) readilylose carbon monoxide by heating, according to the general behaviour ofthe alphaketo esters which are heat-sensitive (cf. J. D. Roberts et al.,Basic Principles of Organic Chemistry", Benjamin lnc., New York, i965,page 54l Conversely, by carrying out the Claisen reaction under theconditions of the present invention, such emission of carbon monoxide isno longer experienced. More particularly, the

l,3-bis-( 2-carboethoxychromone-5-iloxy )-2- hydroxypropane (II, R C- Hx cn (3H c11 has the aspect of a straw-yellow crystal having a meltingpoint of l86l88C and an absolute chromatographic purity. Conversely, theproduct "which is obtained, in a much lesser amount, by workingaccording to the suggestions of the British Pat. Specn. No. 1,144,905 isof a darker shade, is difficult to purify and melts at l80-l 82C.Consequently, with the method of the present invention, also thebi-sodium salt obtained from the corresponding ester by saponificationwith NaOH, is directly obtained in a pure state without any necessity offurther purification steps.

The considerations developed above make it apparent that themodifications introduced in the synthesis run of the products having theformula (ll) substantially improve the times, temperatures, yields,costs and quality of the chromones (ll) and their salts (l) and permitthat the isolation of the intermediates (lV) may be dispensed with. Suchmodifications were absolutely unpredictable on the basis of what hadbeen disclosed in the technical literature and more particularly in theabove indicated patents.

It is particularly to be emphasized that, to the ends of the Claisenreaction, it was deemed preferably that aprotic solvents had to be used(as clearly suggested by the literature), whereas for the cyclization ofthe product (lV) it is preferable to operate in an alcoholic solution.This is the reason why all the conventional methods for the preparationof the derivatives having the formulas (l) and (II) provide for twodiscrete steps, with the separation and purification of the intermediate(IV).

The invention is illustrated in more detail in the following exampleswhich are given by way of illustration only and without limitation. Moreparticularly, the examples la, lb, lc and 1d are referred to the case inwhich X is 2-hydroxypropyl, whereas in the examples 2a and 2b, X ispropyl.

EXAMPLE 1 a. l,3-bis-( 2-carbethoxychr0mone-5-iloxy )-2- hydroxypropane.

A solution of sodium ethoxide, prepared with l59 grams sodium and 3liters of absethanol, is supplemented, with stirring with 500 grams ofl,3-bis-(2- acetyl-3-hydroxyphenoxy)-2-hydroxypropane. The stirredmixture is then supplemented, dropwise and at a temperature of C, by 950ml. ethyl oxalate and, on completion of the addition, the yellowsolution thus obtained is heated to 4045C during 40 minutes. The mixtureis cooled to 5C and made acidic by addition of a 10 percent solution ofHCl in ethanol. The mixture is heated again with gentle stirring at 50Cfor 30 mins. and is then cooled at 5C with iced water. The bulkyprecipitate is collected under suction washed with ethanol and withwater and then crystallized from liters of tetrahydrofuran in thepresence of 10 grams activated charcoal. By concentrating the filtrateto one tenth of its original volume one obtains 626 grams (yield 86percent of theory) of the product (that is, 1,3-bis-(2-carbethoxychromone-5-iloxy)-2- hydroxypropane) of a lightstraw-yellow color and a m.p. of l86-l88C, which is unitary tochromatographic analysis on a thin layer. (Silica-gel HF; eluent:dioxan-ethyl acetate-tetrahydrofuran 60/20/20, visualization with UVlight 250 millimicrons and with 0.1N 1

b. l,3-bis-(2-carboxychromone-S-iloxy)-2- hydroxypropane (bi-sodiumsalt).

A suspension of 626 grams of l,3-bis-(2-carboethoxychromone-S-iloxy)-2-hydroxypropane, finely powdered, in 5liters of 95 percent ethanol is treated with 2.05 equivalents of 2N NaOHand heated with stirring at 70C during 30 minutes. The fine crystalwhich separates is collected in hot conditions by suction and is washedby slurrying with lukewarm ethanol until neutrality of the product isreached. Upon drying an oven, there are obtained 635 grams (91 percentof theory) of the bisodium salt of l,3-bis-(2-carboxychromone-S-iloxy)-2-hydroxypropane tetrahydrate as virtuallycolorless crystals with a m.p. of 267-270C (decomp). The substance isunitary to thin layer chromatography (Silica-gel HF; eluent 95% EtOH NHOH H O 100/16/12; visualization with UV light millimicrons and with 0.1N

c. l,3-bis-(2-carboxychromone'5-iloxy)-2- hydroxypropane.

An aqueous solution of the bisodium salt of l,3-bis-(2-carboxychromone-5-iloxy)-2-hydroxypropane is made acidic to Congo redwith diluted hydrochloric acid. The precipitate is collected undersuction and dried and l,3-bis-(2-carboxychromone-5-iloxy)-2-hydroxypropane monohydrate is obtained with virtually theoretic yieldsas a practically colorless crystal having a m.p. of 243245C (dec.).

(1. Dipiperidine salt of 1,3-bis-(2-carboxychromone- ;ilo ylz2-hy rtypropans.

An aqueous solution of 1,3-bis-(2-carboxychromone-5-iloxy)-2-hydroxypropane is treated with two equivalents of piperidine.The solution which is obtained is concentrated in a vacuo and cooled togive with virtually quantitative yields the dipiperidine salt ofl,3-bis- (2-carboxychromone 5jloxy)-2-hydroxypropane.

EXAMPLE 2 a. l,3-bis-( 2-carboethoxychromone-5-iloxy propane.

By adopting the same procedure as in Example la, I38 grams ofl,3-bis-(2-acetyl-3-hydroxyphenoxy)- propane are condensed with diethyloxalate and sodium ethoxide at room temperature during 2 hours. Thereare obtained 185 grams (89 percent of theory) of l,3-bis-(2-carboethoxychromone-5-iloxy)-propane having a m.p. of l86l88C(decomp).

b. Bisodium salt of l,3-bis-(2-carboxychromone-5- iloxy)-propane.

By adopting the same procedure of example lb, 185 grams ofl,3-bis-(2-carboethoxychromone-5-iloxy)- propane have been treated with2.04 equivalents of 2N NaOH to give grams (96 percent of theory) of thebisodium salt of l,3-bis-(2-carboethoxylchromone-5- iloxy)-propanemonohydrate in the form of virtually colorless crystals.

What is claimed is:

l. [n a method for the preparation of a 5-hydroxy-2-carboxychromone ofthe formula:

0 o I ll wherein X is alkylene or hydrogen-substituted alkylene grouphave from three to seven carbon atoms and carrying an alcoholic (CHOH)group inserted in the alkylene chain, by alkaline hydrolysis of thecorresponding lower alkyl esters, said esters being prepared startingfrom the corresponding bis-phenoxy deriva- 'tive, the improvement whichcomprises reacting the corresponding bis-phenoxy derivative of theformula:

1. IN A METHOD FOR THE PREPARATION OF A 5-HYDROXY-2-CARBOXYCHROMONE OFTHE FORMULA:
 2. A method according to claim 1 wherein said alcoholicprotic solvent is ethanol.
 3. A method according to claim 1 wherein thereaction with the dialkyl oxalate is carried out at room temperature.